There is a fundamental gap in understanding the extent to which treatment of bacterial biofilms with combinations of drug compounds may synergistically kill the biofilm colonies. Continued existence of this gap represents an important problem because, until it is filled, the development of co-therapy systems for clinical use in chronic infections will be delayed. The long term goal of this research is to develop novel and effective inhalable strategies for the treatment of respiratory infections. The objective in this application is to identify compounds that, when delivered in combination, more effectively eradicate Pseudomonas aeruginosa biofilms. Our central hypothesis is that delivery of selected dispersion compounds will increase the sensitivity of P. aeruginosa to antibiotic treatment, resulting in improved outcomes in a murine model. This hypothesis has been formulated on the basis of preliminary data produced in the applicants' laboratories. Once it is known which combinations of compounds can synergistically enhance biofilm killing in vitro and in vivo, new treatment strategies based on these compounds can be clinically developed. The proposed research is innovative because it focuses on enhancing the effectiveness of traditional antibiotics with the use of dispersion compounds that target disruption of the biofilm. The proposed research is significant because it is expected to provide knowledge needed for the clinical development of inhalable co-delivery aerosols for the treatment of bacterial biofilms.